1. Field of the Invention
This invention is directed to new epipodophyllotoxin glucoside derivatives, to methods of preparing these new derivatives, and to the therapeutic use of these new derivatives. More particularly, this invention is directed to oxidized derivatives of epipodophyllotoxin glucosides having substantial water solubility. This substantial water solubility greatly increases the effectiveness of the new compounds both in ease of delivery and in elimination of the harmful clinical side effects associated with the solvent delivery systems employed with the precursor glycosides known to the prior art.
2. Description of the Background Art
Podophyllotoxin has the structural formula (I): ##STR2## It is a naturally occurring compound which may be isolated from the roots and rhizomes of the American Podophyllum peltatum L. This compound, as well as some other structurally closely related lignans and lignan glycosides are known to exert a powerful and specific inhibition of mitosis. I. W. Kaplan, New Orleans Med. Surg. J., 94:388 (1942); B. J. Sullivan and H. J. Wechsler, Science, 105:433 (1947); M. G. Kelly et al., J. Nat. Cancer Inst., 14:967 (1954). However, clinical trials involving systemic application of these tumor-damaging agents have proven to be unsatisfactory due to nonspecific toxicity of the various compounds.
Systematic chemical modification of the podophyllotoxin molecule has led to several therapeutically useful semi-synthetic preparations which are well absorbed enterally and possess a favorable ratio between anti-mitotic activity and non-specific toxicity. See Keller-Juslen, Journal of Medicinal Chemistry, (1971) Vol. 14, No. 10., pp. 936-940. Of particular interest are the 4'-demethylepipodophyllotoxin glucoside derivatives having the structural formula (II): ##STR3## in which R.sub.1 is hydrogen, and R.sub.2 is an alkyl; alkenyl; cycloalkyl; 2-furyl; 2-thienyl; aryl; aralkyl; and aralkenyl, wherein the aromatic ring may optionally be substituted, preferably by one or more of hydroxy, alkyl, alkoxy, nitro, or halogen radicals. R.sub.1 and R.sub.2 may also each be an alkyl radical, or R.sub.1 and R.sub.2 together with the carbon atom to which they are attached, may form a saturated cycloaliphatic ring having five or six carbon atoms. These compounds, and the method for producing them, are disclosed in U.S. Pat. No. 3,408,441 to Wartburg et al. and U.S. Pat. No. 3,524,844 to Keller-Juslen et al. As disclosed in U.S. Pat. No. 3,524,844 to Keller-Juslen et al., compounds having the general formula (II) may be prepared by reacting 4'-demethylepipodophyllotoxin-beta-D-glucoside of the general formula (III): ##STR4## with a compound having the general formula (IV) ##STR5## where R.sub.1 and R.sub.2 are as described above. Alternatively the compound (III) may be reacted with a lower acetal or ketal thereof, in the presence of an acid, suitably a Lewis or sulphonic acid catalyst. The reaction is usually carried out in the absence of moisture and preferably carried out in the absence of oxygen, e.g., by providing a nitrogen atmosphere. Suitable Lewis acid catalysts include anhydrous zinc chloride. Suitable sulphonic acid catalysts include p-toluene sulphonic acid. Dimethylacetal, diethylacetal, the cyclic ethylene acetal or the corresponding ketals may be used as acetals or ketals of the compounds of formula (IV). It is preferred, in order to obtain a higher yield from the condensation, to remove the resulting reaction water or the resulting lower alcohol by azeotropic distillation in a vacuum at a low temperature or, in the case where water of reaction is formed, to use a catalyst which also has water-binding properties.
Among the compounds described above, two compounds corresponding to the general formula (II) are of particular interest and have been explored extensively. Etoposide corresponds to the general formula (II) wherein R.sub.1 is hydrogen and R.sub.2 is methy. Teniposide corresponds to the general formula (II) wherein R.sub.1 is hydrogen and R.sub.2 is 2-thienyl ##STR6##
Research regarding these two compounds is described extensively by I. Jardine in "Anticancer Agents Based On Natural Product Models," Medicinal Chemistry, Vol. 16 (1980), pp. 319-351. As disclosed therein, both teniposide and etoposide have been found to be active in Ehrlich ascites tumor, sarcoma 37 and 180, Walker carcinosarcoma, mouse ependymoblastoma, and a variety of murine leukemias, as well as L-1210. Additionally, both compounds are effective in Hodgkin's disease and non-Hodgkin's lymphomas, especially reticulum-cell sarcoma. Teniposide shows definite anti-tumor activity in brain tumors and bladder cancer, while etoposide is active in acute nonlymphocytic leukemia, in small-cell lung cancer, and possibly in ovarian and thyroid cancer. However, in spite of the extreme importance as anti-cancer agents of these two compounds, the clinical usefulness of the drugs is significantly diminished by the fact that they are not, for practical purposes, water soluble. This lack of water solubility requires that they be formulated in a mixture of organic solvents, the solvents themselves exhibiting serious clinical side effects.
Thus a need has continued to exist for new, pharmacologically useful, epipodophyllotoxin glucoside derivatives having improved water solubility for use in anti-cancer therapy. The discovery of water soluble quinone derivatives makes possible clinical anti-tumor treatment which avoids the undesirable side effects which are a consequence of organic solvents employed previously in the administration of the prior art epipodophyllotoxin glucoside derivatives.